Enantioselective ring opening reaction of meso-epoxides with aromatic and aliphatic amines catalyzed by magnesium complexes of BINOL derivatives

Article abstract of DOI:10.1002/ejoc.201001222

Catalyzed by the Mg complexes of BINOL derivatives, the enantioselective ring opening reaction of various meso-epoxides proceeded smoothly with either aromatic or aliphatic amines as the nucleophiles to afford the corresponding chiral β-amino alcohols in

Full text of DOI:10.1002/ejoc.201001222

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201001222
Enantioselective Ring Opening Reaction of meso-Epoxides with Aromatic and
Aliphatic Amines Catalyzed by Magnesium Complexes of BINOL Derivatives
Hongli Bao,[a,b] Jiang Wu,[a] Hongji Li,[a] Zheng Wang,[a] Tianpa You,[b] and
Kuiling Ding*[a]
Keywords: Asymmetric catalysis / Epoxides / Amino alcohols / Amines / Magnesium
Catalyzed by the Mg complexes of BINOL derivatives, the
enantioselective ring opening reaction of various meso-epox-
ides proceeded smoothly with either aromatic or aliphatic
amines as the nucleophiles to afford the corresponding chiral
β-amino alcohols in moderate-to-high yields with good to ex-
cellent enantioselectivities.
herent problem of catalyst deactivation, caused by the
stable complex formation of the Lewis acid catalyst with
the amine nucleophile and/or the generated β-amino
alcohol product.[2,6] Nevertheless, some simple metal salts
have been used as efficient achiral catalysts in the non-
asymmetric ring opening aminolysis of epoxides even with
aliphatic amines.[7] Thus, it occurred to us that a suitable
combination of a Lewis acid metal and a chiral chelating
ligand might provide an adequate control of the competitive
coordination to the metal center, i.e. to favor the preferen-
tial coordination and activation of the epoxide without sat-
uration of the active site, and hence may allow for good
turnovers and respectable ee values in the reaction by using
either aromatic or aliphatic amines. Chiral complexes of
strongly oxophilic magnesium(II) species seems a promising
option in this respect, which have found increasing use in
asymmetric catalysis of a variety of synthetic reactions.[8]
Herein we report the development of efficient BINOLate/
Mg catalysts for the asymmetric ring opening reaction of
meso epoxides with both aromatic and aliphatic amines as
the nucleophiles. The reactions proceed smoothly under
mild conditions to afford the corresponding chiral β-amino
alcohols in moderate to excellent yields with high enantio-
selectivities.
Introduction
Optically active β-amino alcohols are compounds of
great interest in organic chemistry as building blocks for
biologically active compounds and as chiral auxiliaries or
ligands for applications in asymmetric synthesis.[1] The
asymmetric ring opening reaction of meso- or racemic epox-
ides with amines affords a simple route to optically enriched
β-amino alcohols.[2] Over the last decade or so, a variety of
chiral catalysts have been developed for this reaction,
mostly including Lewis acid complexes based on various
metal ions.[3] Despite this fact, however, in each case a wide
generality with respect to the amine nucleophiles has not
yet been achieved. Especially, the catalytic asymmetric ring
opening of epoxides with aliphatic amines is a challenging
goal, and so far, very few of the reported systems afford
respectable ee values in this type of reaction. In this respect,
Inaba et al. have shown that TiIV complexes of enantiopure
1,1Ј-bi-2-naphthol (BINOL) are efficient and highly enan-
tioselective catalysts in the ring opening of 3,5,8-trioxabicy-
clo[5.1.0]octane with alkylamines to afford 2-amino-1,3,4-
butanetriols in high optical purity.[4] We have investigated
the mechanism of this reaction and provided spectroscopic
evidence of the active species.[5] However, the protocol was
found to be effective only for this chelating epoxide sub-
strate, whereas the common meso-epoxides tested did not
undergo reaction. It is widely recognized that, in the asym-
metric ring opening reaction of epoxides, strongly Lewis
base aliphatic amines as the nucleophiles can have an in-
Results and Discussion
We initiated the study by investigating the ring opening
reaction of cyclohexene epoxide 1 with aniline, using a chi-
ral magnesium complex generated in situ by combination
of a substoichiometric amount of (R)-BINOL and Bu2Mg
as the catalyst. As shown in Table 1, the reactions generally
proceeded smoothly with moderate enantiocontrol, but
both the activity and enantioselectivity are strongly influ-
enced by the variation in the reaction conditions, including
the molar ratios of BINOL and Bu2Mg (Entries 1–7), sol-
vents (Entries 5, 8–13), as well as the temperature (Entries
[a] State Key Laboratory of Organometallic Chemistry,
Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences,
345 Lingling Road, Shanghai 200032, China
Fax: +86-21-6416-6128
E-mail: kding@mail.sioc.ac.cn
[b] Department of Chemistry,
University of Science and Technology of China,
Hefei 230026, Anhui, China
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201001222.
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Catalysis of Enantioselective Ring Opening Reaction of meso-Epoxides
5, 14–18). For the reactions performed at room temperature ene sulfonic acid, and 4-Å molecular sieves, and the results
in toluene, increasing the molar ratios of Bu2Mg/BINOL were summarized in Table 2. A marginal enhancement of
from 0.5 to 1.5 led to considerable improvement in the yield the ee value of 2 from 54 to 61% was obtained with a
of 2 (58–99%, Entries 1–7). However, the best ee value proper amount of Ph3PO or benzoic acid (ca 5 mol-%) as
(53%) was attained with a Bu2Mg/BINOL ratio of 1.3 (En- the additive (Entries 4 and 6).[9] Notably, the addition of
try 5), which was thus kept unchanged in the studies there- 1 mol-% MeLi to the reaction system at 35 °C under a cata-
after. A survey of the solvent indicated that toluene is the lyst loading of 1 mol-% resulted in a drastic improvement
optimal choice in terms of reactivity and ee values (Entries of the ee value of 2 to 73%, albeit accompanied with a
5 vs. 8–13), while the coordinating solvents THF and aceto- slight drop in yield (Entries 14 vs. 13).[10] A control experi-
nitrile led to rather poor results (Entries 9 and 13). Under ment showed that BINOL/MeLi alone is not effective for
otherwise identical conditions (the use of toluene and a the ring opening reaction of 1 under otherwise identical
Bu2Mg/BINOL ratio of 1.3), the reaction proceeded some- conditions, thus confirming the synergistic effect of the Li-
what sluggishly at lower temperature (0 °C) with a slightly containing species in the BINOLate/Mg-mediated cataly-
reduced ee value for 2 (Entries 5 vs. 14), while excellent sis.[11] Several other alkaline metal species were also tested
yields and moderate ees were attained at elevated tempera- as the additives in the reaction (Entries 15–17). Even
tures (Entries 15–17). Finally, the reaction in toluene at though they also exhibited some beneficial effect on the
35 °C proceeded smoothly under a reduced catalyst loading enantioselectivity, in each case the ee value was inferior to
(1 mol-%), wherein product 2 was isolated in excellent yield that with the MeLi additive.
with a moderate level of enantioselectivity (Entry 18).
Table 2. Additive effects in the asymmetric ring opening reaction
of epoxide 1 and aniline catalyzed by the (R)-BINOL/Bu2Mg com-
plex.[a]
Table 1. Optimization of the asymmetric ring opening reaction of
epoxide 1 and aniline catalyzed by the (R)-BINOL/Bu2Mg com-
plex.[a]
Entry Additive (mol-%)
Yield [%][b]
ee [%][c]
1
none
DMAP (6)
Et3N (10)
TPP(O) (5)
TPP (5)
PhCOOH (5)
4-nitrobenzoic acid (5)
adipic Acid (5)
l-leucine (5)
cinnamic acid (5)
TsOH (3)
4 Å MS (50 mg)
none
MeLi (1)
95
63
85
99
99
98
99
99
97
97
98
99
99
87
94
75
90
55
19
36
61
51
61
57
45
51
54
53
0
55
73
57
60
67
2[d]
3[d]
4
Entry X/10 Solvent
T [°C] Time [h] Yield [%][b] ee [%][c]
1
2
3
4
5
6
7
8
0.5
1.0
1.1
1.2
1.3
1.4
1.5
1.3
1.3
1.3
1.3
1.3
1.3
1.3
1.3
1.3
1.3
1.3
toluene
toluene
toluene
toluene
toluene
toluene
toluene
CH2Cl2
THF
pentane
CHCl3
Et2O
CH3CN
toluene
toluene
toluene
toluene
toluene
25
25
25
25
25
25
25
25
25
25
25
25
25
0
16
16
16
16
16
16
16
24
24
24
24
24
24
36
6
58
74
93
92
94
96
99
87
37
97
90
78
34
89
99
98
98
94
25
38
45
44
53
50
46
42
18
34
37
29
21
46
54
55
48
53
5
6
7
8
9
10
11
12
13[e]
14[e]
15[e]
16[e]
17[e]
9
10
11
12
13
14
15
16
17
18[d]
LiCl (1)
NaH (1)
nBuLi (1)
35
50
70
35
[a] Unless otherwise noted, all the reactions were carried out in
toluene at 35 °C by using 1.0 mmol of aniline and 1.5 mmol of 1
in the presence of 10 mol-% BINOL and 13 mol-% of Bu2Mg. [b]
The yield of isolated product based on aniline. [c] Determined by
HPLC on a chiral AD column. In each case, the absolute configu-
ration was found to be (1R,2R) by comparison of the [α]D value
with that of the literature (see ref.[3h]). [d] Room temperature, 24 h.
[e] The reactions were carried out in the presence of 1.0 mol-%
BINOL and 1.3 mol-% Bu2Mg.
2
2
16
[a] Unless otherwise noted, all the reactions were performed with
1.0 mmol of aniline and 1.5 mmol of 1 in the presence of 10 mol-%
BINOL and a specified amount of Bu2Mg. [b] The yield of isolated
product based on aniline. [c] Determined by HPLC on a chiral AD
column. In each case, the absolute configuration was found to be
(1R,2R) by comparison of the [α]D value with that of the literature
(see ref.[3h]). [d] The loading of (R)-BINOL is 1 mol-%.
Subsequently, a variety of BINOL derivatives were scre-
ened as the ligands for the Bu2Mg/MeLi catalyzed reaction.
Encouraged by these results, we attempted to further im- As shown in Table 3, the partially reduced BINOLs (R)-
prove the enantioselectivity of the catalysis by introduction 5,6,7,8-tetrahydro-1,1Ј-bi-2-naphthol (H4-BINOL)[12] and
of various additives into the reaction system. A variety of (R)-5,5Ј,6,6Ј,7,7Ј,8,8Ј-1,1Ј-bi-2-naphthol
(H8-BINOL)[13]
additives were examined, including Lewis bases (Ph3P, exhibited a comparable enantioselectivity as BINOL itself,
Ph3PO, Et3N, DMAP), carboxylic acids (benzoic acid, 4- but the reactivity was somewhat inferior (Entries 2, 3 vs. 1).
nitrobenzoic acid, adipic acid, and cinnamic acid), p-tolu- The 6,6Ј-dihalogen substituted BINOLs showed excellent
Eur. J. Org. Chem. 2010, 6722–6726
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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H. Bao, J. Wu, H. Li, Z. Wang, T. You, K. Ding
SHORT COMMUNICATION
reactivity, but with slightly decreased ee values (Entries 4,
Remarkably, the catalytic system generated in situ by
5). The 3,3Ј-diiodine substituted BINOL gave a relatively mixing of BINOL analogues and Bu2Mg were also found
poor result (Entry 6), however. Thus, BINOL still turns out effective for the more challenging asymmetric ring opening
to be optimal for this reaction in terms both reactivity and reactions of meso-epoxides and aliphatic amines, as summa-
enantioselectivity.
rized in Table 5. A preliminary survey of the asymmetric
ring opening of epoxide 1 with isopropylamine, with the
BINOLate/Bu2Mg/MeLi catalytic system optimized above,
gave the corresponding amino alcohol 11 in 62% yield with
74% ee (Entry 1). Interestingly, the same reaction catalyzed
by BINOLate/Bu2Mg alone under otherwise identical con-
ditions led to a significant enhancement in both the yield
(82%) and ee value (81%) of 11 (Entry 2). Further elabora-
tion of the procedure by using the partially reduced (R)-
BINOL derivative, (R)-H4-BINOL, instead of BINOL as
the ligand led to a substantial increase in both yield (90%)
and ee value (94%) of the product (Entry 3). Subsequently,
the (R)-H4-BINOL/Bu2Mg system was extended to the ca-
talysis of reactions between meso-epoxides and aliphatic
amines (Entries 4–9). Good to excellent reactivity was ob-
served in most cases. Especially, the reactions involving
sterically bulky isopropyl or tert-butylamines gave the cor-
responding amino alcohols in high ee values (81–94%, En-
tries 3, 4, 7–9).
Table 3. Ligand screening for BINOLate/Bu2Mg/MeLi-catalyzed
ring opening reaction of epoxide 1 with aniline.[a]
Entry Ligand
Yield [%][b] ee [%][c]
1
2
3
4
5
6
(R)-BINOL
(R)-H4-BINOL
(R)-H8-BINOL
(R)-6,6Ј-Br2-BINOL
(R)-6,6Ј-I2-BINOL
(R)-3,3Ј–I2-BINOL
87
68
63
92
91
22
73
76
71
67
68
16
[a] All reactions were performed with 1.0 mmol of PhNH2 and
1.5 mmol of 1 in toluene (1 mL) at room temperature. [b] The yield
of isolated product based on aniline. [c] Determined by HPLC on
a chiral AD column. In each case, the absolute configuration was
found to be (1R,2R) by comparison of the [α]D value with that of
the literature (see ref.[3h]).
Table 5. (R)-H4-BINOL/MgBu2-catalyzed enantioselective ring
opening of epoxides with aliphatic amines.[a]
Under the optimized reaction conditions, the enantio-
selective ring opening aminolysis of epoxide 1 was exam-
ined with a variety of aniline derivatives as nucleophiles. As
shown in Table 4, the corresponding chiral β-amino
alcohols 2–10 were generally obtained in moderate to high
yields with good ee values (up to 82%, Entry 6).
Table 4. The enantioselective ring opening reactions of epoxide 1
and aromatic amines catalyzed by BINOLate/Bu2Mg/MeLi sys-
tem.[a]
Entry ArNH2
Yield [%][b] ee [%][c]
[a] All reactions were performed with 1.5 mmol of the amines and
1.0 mmol of the epoxide in toluene (1 mL). [b] The yield of the
isolated product based on the epoxide. [c] ee values were deter-
mined by chiral GC (11, 12, 14–17) or HPLC (13) analysis. Abso-
lute configurations were not assigned. [d] The reaction was carried
out in toluene at room temperature for 48 h, with BINOLate/
Bu2Mg/MeLi (0.01:0.013:0.01 molar equiv. of epoxide 1) as the cat-
alyst. [e] Same as Entry 1, with the exception that MeLi was not
used in this case.
1
PhNH2
87
55
92
90
82
73
75
90
75
71
73 (2)
65 (3)
65 (4)
69 (5)
80 (6)
82 (6)
69 (7)
75 (8)
72 (9)
72 (10)
2
3
4
3-CH3OC6H4NH2
2-CH3OC6H4NH2
4-CH3OC6H4NH2
3-CH3C6H4NH2
3-CH3C6H4NH2
2-CH3C6H4NH2
4-C2H5C6H4NH2
3,5-(CH3)2C6H3NH2
3-IC6H4NH2
5
6[d]
7
8
9
10
[a] All reactions were performed with 1.0 mmol of aromatic amines
and 1.5 mmol of epoxide 1 in toluene (1 mL). [b] The yield of iso-
lated product based on the amine. [c] Determined by chiral HPLC.
The absolute configuration of the major enantiomer (1R,2R) was
assigned by comparison of the rotation values in the literature (see
ref.[3a,3h]) or by analogy.
Conclusions
In summary, the chiral BINOLate/Bu2Mg complex was
found to be efficient for enantioselective catalysis of ring
opening aminolysis of meso-epoxides under mild condi-
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Catalysis of Enantioselective Ring Opening Reaction of meso-Epoxides
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Acknowledgments
Financial support from the National Natural Science Foundation
of China (No. 20923005, 20821002), the Chinese Academy of Sci-
ences, the Major Basic Research Development Program of China
(Grant No. 2010CB833300), the Science and Technology Commis-
sion of Shanghai Municipality is gratefully acknowledged.
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A Higher or lower loading of the additives resulted in a drop
in the ee values of 2.
[10]
The reaction of 1 and aniline catalyzed by BINOL/Bu2Mg/
MeLi was found to be highly sensitive to the moisture brought
adventitiously into the system. Control experiments showed
that the presence of water is particularly detrimental to the
reaction, which leads to a drastic decrease in both the yield
and the ee values of the product, and even a reversal of the
sense of asymmetric induction. For details, see Figure S1 in the
Supporting Information.
Although the exact nature of the cooperative effect is still not
clear at the present stage, it is tempting to speculate that some
supramolecular Mg/BINOL/Li generated in situ by self-as-
sembly should be responsible for the behavior. For reviews on
cooperative bimetallic catalysis, see: a) M. Shibasaki, N. Yoshi-
kawa, Chem. Rev. 2002, 102, 2187–2209; b) J. A. Ma, D. Cah-
[11]
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SHORT COMMUNICATION
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Received: August 30, 2010
Published Online: November 9, 2010
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